ABSTRACT The transmission of diseases including malaria, Dengue fever, and West Nile virus occurs when a mosquito takes a blood meal from a human host. With increased resistance to drugs 1, 2, insecticides and repellents 3, 4, and the effects of global warming leading to extended habitats for these mosquitoes, including in the USA, there is a continued need to develop new methods to prevent the transmission of these diseases. For mosquitoes, blood-feeding is driven by semiochemicals that emanate from human sweat and skin 7. Therefore, disrupting the normal responses to these ?odorants? represents one alternative approach to prevent disease transmission by these mosquitoes (reviewed in 8). In the mosquito olfactory system, odorant binding proteins (OBPs) play a central role in transporting semiochemicals to the chemosensory receptor complex to elicit a behavioral response. Recent studies have discovered that in Ae. aegypti two OBPs, AaegOBP10 and AaegOBP22, directly regulate the blood-feeding behavior of this mosquito 6. Moreover Dengue virus infection of the mosquito led to an increased expression of these two OBPs suggesting that virus infection increases the chemosensory responses associated with blood feeding. Subsequently, knockdown of these two OPB genes resulted in a ~30-45% reduction in the numbers of mosquitoes that bite. Therefore, we hypothesize that targeting AaegOBPs 10 and 22 activities will disrupt normal mosquito behavior and help to control the transmission of Dengue virus by Ae. aegypti. Our overall goal is to discover novel molecules that can disrupt OBP function and thereby mosquito blood feeding behaviors. In this project we will (1) define the tissue specific contribution of each target OBP to blood feeding and host seeking. (2) Determine if targeting both OBP10 and 22 simultaneously represents a better strategy for reducing blood feeding. (3) Determine the three-dimensional structures of each OBP and how these change upon binding to ligands so that we can (4) perform high throughput in silico screens to discover lead compounds that bind with high affinity and so maximize the potential to disrupt normal OBP function. The discovery of compounds that can target OBP function and disrupt blood feeding behaviors would have a direct impact on public health as it would open up new avenues to prevent the transmission of major mosquito borne diseases including Dengue virus, malaria, West Nile virus and emerging arboviruses infections including chikungunya and Zika.